RNA-based medicine: from molecular mechanisms to therapy.

RNA-based therapeutics have the potential to revolutionize the treatment and prevention of human diseases. While early research faced setbacks, it established the basis for breakthroughs in RNA-based drug design that culminated in the extraordinarily fast development of mRNA vaccines to combat the COVID-19 pandemic. We have now reached a pivotal moment where RNA medicines are poised to make a broad impact in the clinic. In this review, we present an overview of different RNA-based strategies to generate novel therapeutics, including antisense and RNAi-based mechanisms, mRNA-based approaches, and CRISPR-Cas-mediated genome editing. Using three rare genetic diseases as examples, we highlight the opportunities, but also the challenges to wide-ranging applications of this class of drugs.

CRISPR memories in single cells.

CRISPR-Cas systems allow bacteria to memorize prior infections as a means to combat the same invader if it attempts another attack in the future. While the underlying mechanisms of this bacterial immunity have been intensely studied over the past decade, little attention has been paid to CRISPR defense at the single-cell level. In their recent work, Brouns and colleagues (McKenzie et al, 2022) track memory acquisition and defense in individual cells and find a wide range of temporal dynamics that shape how a cell population experiences and combats an active infection.

The chromodomain helicase Chd4 is required for Polycomb-mediated inhibition of astroglial differentiation.

Polycomb group (PcG) proteins form transcriptional repressor complexes with well-established functions during cell-fate determination. Yet, the mechanisms underlying their regulation remain poorly understood. Here, we extend the role of Polycomb complexes in the temporal control of neural progenitor cell (NPC) commitment by demonstrating that the PcG protein Ezh2 is necessary to prevent the premature onset of gliogenesis. In addition, we identify the chromodomain helicase DNA-binding protein 4 (Chd4) as a critical interaction partner of Ezh2 required specifically for PcG-mediated suppression of the key astrogenic marker gene GFAP. Accordingly, in vivo depletion of Chd4 in the developing neocortex promotes astrogenesis. Collectively, these results demonstrate that PcG proteins operate in a highly dynamic, developmental stage-dependent fashion during neural differentiation and suggest that target gene-specific mechanisms regulate Polycomb function during sequential cell-fate decisions.

Polycomb silencers control cell fate, development and cancer.

Polycomb group (PcG) proteins are epigenetic gene silencers that are implicated in neoplastic development. Their oncogenic function might be associated with their well-established role in the maintenance of embryonic and adult stem cells. In this review, we discuss new insights into the possible mechanisms by which PcGs regulate cellular identity, and speculate how these functions might be relevant during tumorigenesis.

Ras oncogene and inflammation: partners in crime.

It is well established that Ras oncogenes facilitate neoplastic conversion by stimulating tumor cell growth, survival and motility. However, current studies have indicated that the role of Ras in malignant transformation extends beyond these cell-intrinsic effects to include the establishment of a pro-tumorigenic host environment. We have recently demonstrated that Ras-induced secretion of the chemokine Interleukin-8 (CXCL-8/IL-8) elicits a local inflammatory reaction that is critical for neo-vascularization and sustained tumor growth. Our data identify a novel mechanism by which the Ras oncogene promotes tumor-host interactions that are essential for cancer progression, and suggest that CXCL-8 could serve as a surrogate marker for in-vivo Ras activity.

Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis.

The role of Ras oncogenes in promoting cellular transformation is well established. However, the contribution of Ras signaling to interactions between tumor cells and their host environment remains poorly characterized. Here, we demonstrate that the inflammatory mediator interleukin-8 (CXCL-8/IL-8) is a transcriptional target of Ras signaling. Using a tumor xenograft model, we show that Ras-dependent CXCL-8 secretion is required for the initiation of tumor-associated inflammation and neovascularization. Collectively, our data identify a novel mechanism by which the Ras oncogene can elicit a stromal response that fosters cancer progression.